IBD and the microbiome: strong relationship, casual affair or total indifference?

By now, most of us have learned that human beings have co-existed with bugs since the beginning of time and that we bear trillions of microbes in our body (the “microbiome”) — mostly located in the gut. There, they appear to act as a digestive organ, a training tool for the immune system, and a guardian of dangerous infections — key roles in several vital health functions.

In the last 15 years, there has been an explosion of interest in the microbiome field. A PubMed search using the keywords “gut microbiome” retrieves, at the time of this writing, more than 9,000 citations starting with one in 2002 and growing to 2,777 in 2017. Many human diseases have been linked to the gut microbiota. Among those, the most studied are the inflammatory bowel diseases (IBD) — both ulcerative colitis (UC) and Crohn’s disease (CD) — with the number of PubMed yearly citations for “microbiome and IBD” climbing steadily from one to 277 in the last 15 years. Great initiatives such as the American Gut Project and the AGA Center for Gut Microbiome have started to sequence bacterial DNA in the general population and in IBD patients. Multiple conferences on the subject are organized every year. Research funding (both federal and non-federal) has increased steadily over the years. Major pharmaceutical companies have created ad hoc enterprises to develop microbiome-based health solutions for IBD and many other diseases. In short, this appears to be a booming scientific and business enterprise which could potentially change our understanding and treatment of many medical issues, including IBD.

But, at least for IBD, what is this all based on? In one word: dysbiosis. The microbiome of IBD patients is significantly different from that of healthy controls — hence, given the complex and vital role of bacteria in maintaining our wellbeing, it is assumed that the disruption of their “normal” profile could be at the basis of IBD. Typical alterations found in IBD patients compared to healthy controls include a decrease in diversity and in Bacteroides, Firmicutes, Clostridia, Ruminococcaceae, Bifidobacterium, Lactobacillus, and F. prausnitzii species; an increase in Gammaproteobacteria; and the presence of adherent invasive E.coli and Fusobacterium. Altered microbial function, metabolism and membrane transport has also been reported in IBD patients. All these alterations are significant and reproducible.1 Also, in vivo and in vitro studies suggest that bacteria are needed for IBD to develop.

The problem is, we still don’t know whether the dysbiosis in IBD is the cause or the consequence — i.e. bacterial adaptation for survival — of the disease state. Obviously, this is a nontrivial question as it relates to disease understanding and treatment.

Current evidence supports both views.2 For example, the degree of inflammation impacts the microbial profile in IBD. In addition, a dysbiosis similar to that described in IBD has been observed in patients with nonspecific intestinal damage. Effective IBD medications (such as anti-TNF-α agents) seem to restore, at least in part, many of the microbial defects in IBD patients. By contrast, drugs affecting the microbial community — such as antibotics and probiotics — are not effective long-term therapies for IBD. Furthermore, a number of independent factors are known to affect the microbial community in the gut (both in health and disease) including age, diet (including food additives) and smoking. These observations suggest that local changes in the intestinal mucosa following the disease onset might be the cause of the altered microbial profile in IBD.

The problem is, we still don’t know whether the dysbiosis in IBD is the cause or the consequence — i.e. bacterial adaptation for survival — of the disease state.

Other findings suggest a potential etiologic role of the microbiome in IBD. For example, dysbiosis seems to be associated with genetic polymorphisms. Moreover, immune-mediated colitis in genetically susceptible mice can be provoked with single commensal bacterial species. Also, recent studies have shown that fecal microbiota transplant might be effective to treat UC — at least in the short to medium term. While some studies have shown that ethnicity and geography might have an impact on microbial diversity in IBD patients, other studies have shown striking similarities between Eastern and Western IBD patients, including the microbial profile.

Interestingly, dysbiosis and altered microbial metabolism can be detected in healthy cohabiting partners of IBD patients — thus implying that the microbiome might be partially transferred from patients to healthy individuals. Indeed, cohabitation is a way to share our microbial cell population with family members, or even with our dogs. However, spouses of IBD patients (or their dogs!) do not have an increased risk of developing the disease.

There are clearly limitations in understanding some of this research both at the molecular and at the patient level. For example, differences in microbial profile and function might be difficult to identify due to the unique features of protein synthesis in bacteria, to the scarcity of some elements of the microbial community or to the sequencing methods used. Often, stool bacteria are tested. However, it is the intestinal tissue microbiome which more closely represents the intestinal mucosa flora. Likewise, patient and populations’ confounding factors (e.g. diet, local diseases, health care, co-morbidities, etc.) can even be more numerous and difficult to control.

Perhaps the greatest problem in understanding the role of dysbiosis in IBD is the time gap. What we observe today in established IBD patients might not have been necessarily present at the biologic disease onset — several years earlier. A potential solution to this issue is to diagnose IBD very early, at the preclinical stage. My group has already shown that this is possible for CD3 and in principle should be even easier for UC. Such an approach might allow us to look back far enough in time to see how it all began (in addition to potentially providing opportunities to block disease progression). We are currently sequencing intestinal tissue samples from patients at disease onset and comparing them to established CD patients and controls. These data might offer clues about the role of the microbiome in IBD and might guide further research into this issue — as we complete a larger pre-clinical multicenter study in the U.S.4

Clearly the answer might be more complex than the cause-or-effect question that we have asked. The truth might lie in between. For example, Haller and Buttó have hypothesized that in IBD, initial local changes in tissue integrity might lead to focal areas of inflammation resulting in the selection of a dysbiotic bacterial community which might in turn be associated with the propagation of a disease phenotype.5 In other words, dysbiosis could be a consequence of inflammation and yet could drive the process once it has started. While enormous progress has been made in the technology necessary to finely map the microbial population in the gut, we still do not know what it precisely does and if and how it impacts disease. Pursuing knowledge is a noble task. Finding the cause of — or the cure for — IBD is a daunting one.

Dr. Sorrentino has been a consultant for AbbVie, Janssen, Schering-Plough, Centocor, Ferring, Giuliani, Medtronic and TechLab. Dr. Sorrentino is a member of the AGA International Committee.

D. Sorrentino, MD, FRACP, is part of the IBD Center of the Division of Gastroenterology; the Tech Carilion School of Medicine in Roanoke, VA; and the Department of Clinical and Experimental Medical Sciences at the University of Udine School of Medicine in Udine, Italy.